Amino compounds



sified into two distinct groups.

3,142,619 AMINO COMPOUNDS Charles Ferdinand Huebner, Chatham, and Lloyd Benjamin Witkin, Parsippany, N.J., assignors to Ciba Corporation, a corporation of Delaware No Drawing. Filed July 24, 1961, Ser. No. 125,974 4 Claims. (Cl. 167--65) N-CH as its principal representative member, as well as other opium alkaloids with analgesic properties, such as codeine and the like, semi-synthetic morphine-type analogs, e.g. dihydromorphinone, methylhydromorphinone and the like, or totally synthetic analogs, which feature some of the essential structural characteristics of morphine, e.g. meperidine, methadone, 3-hydroxy-N-methyl-morphinan and the like. All of these compounds, having a morphine-type structure, exhibit a strong analgesic effect and are primarily used to combat severe pain, for example, in connection with surgery, injuries and the like.

The second group comprises analgesics, which are primarily used to alleviate pain symptoms caused by spastic conditions, e.g. headaches and the like, or chronic pains, as connected for example, with arthritis and the like, or any other, lesser pain. The compounds of this group are not structurally related to morphine or its analogs, and, generally, their analgesic effect is coupled with some antipyretic properties. The main representative of this group is acetyl-salicylic acid of the formula:

COOH

Additional representative compounds of this second group are other salicyclic acid derivatives, e.g. phenyl salicylate and the like, quinoline carboxylic acids, e.g. cinchophen and the like, anilides, e.g. acetophenetidine and the like,

pyrazolones, e.g. aminopyrin, 4-isopropyl-3-methyl-l,2-

diphenyl-pyrazolone and the like.

A great number of analgesic preparations are known, which contain one single active substance or a combination of more than one analgesic ingredient; ahnost invariably these compositions may be classified into one of the above-mentioned two groups, i.e. the strong analgesic compositions containing as active ingredients those having morphine-type structure or at least essential features of that structure, or the weaker analgesic preparations containing compounds of the analgesic-antipyretic group.

We have now found a new composition and method for the alleviation of pain. The method comprises administering to a host requiring relief from pain, a pharma- United States Patent 3,142,619 Patented July 28., 1964 ceutical composition consisting essentially of an effective amount of Z-arnino-indane having the formula:

hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, as well as those with an organic carboxylic acid having from one to twenty carbon atoms, such as a lower aliphatic monocarboxylic acid, for example, a lower alkane monocarboxylic acid, e.g. formic, acetic, propionic, butyric, isob'utyric, pivalic acid and the like, a lower alkene monocarboxylic acid, e.g. 3-butene carboxylic acid and the like, a hydroxy-lower alkane monocarboxylic acid, e.g. glycolic, lactic acid and the like, a lower alkoxylower alkane monocarboxylic acid, e.g. methoxy-acetic, ethoxy-acetic acid and the like, a lower alkanoyl-lower alkane monocarboxylic acid, e.g. pyruvic acid and the like, a halogeno-lower alkane monocarboxylic acid, e.g. trifluoroacetic, chloroacetic, dichloroacetic, trichloroacetic, bromoacetic acid and the like, a lower aliphatic dicarboxylic acid, for example, a lower alkane dicarboxylic acid, e.g. oxalic, malonic, succinic, methyl-succinic, dimethylsuccinic, glutaric, ot-methylglutaric, a,a-dimethylglutaric, ,B-methylglutaric acid and the like, a lower alkane dicarboxylic acid half ester with a lower alkanol, e.g. succinic acid monomethyl ester, glutaric acid monoethyl ester and the like, a lower alkene dicarboxylic acid, e.g. itaconic, homoitaconic, maleic, citraconic, homocitraconic, pyrocinchonic, xeronic, fumaric acid and the like, a lower alkene dicarboxylic acid halfester with a lower alkanol, e.g. maleic acid monoethyl ester and the like, a hydroxy-lower alkane dicarboxylic acid, e.g. malic, tartaric acid (also in the optically active forms as D-tartaric or L-tartaric acid) and the like, as well as the optically active forms thereof, a lower alkoxy-lower alkane dicarboxylic acid, e.g. a,}9-dimethoxysuccinic and the like, a lower alkoxy-lower alkene dicarboxylic acid, e.g. ethoxymaleic acid and the like, a halogeno-lower alkane dicarboxylic acid, e.g. chlorosuccinic, bromosuccinic acid and the like, a lower aliphatic tricarboxylic acid, for example, a lower alkane tricarboxylic acid, e.g. tricarbalylic acid and the like, a lower alkene tricarboxylic acid, e.g. aconitic acid and the like, a hydroxy-lower alkane tricarboxylic acid, e.g. citric and the like, a cycloaliphatic monocarboxylic acid, such as a cycloalkane monocarboxylic acid in which cycloalkane contains from five to six carbon atoms as ring members, e.g. cyclohexane carboxylic acid and the like, a cycle-aliphatic dicarboxylic acid, such as a cycloalkene dicarboxylic acid in which cycloalkene contains from five to six carbon atoms as ring members, e.g. tetrahydrophthalic acid and the like, a cycloaliphatic-lower aliphatic monocarboxylic acid, such as cyclo-alkyl-lower alkane monocarboxylic acid, in which cycle-alkane contains from five to six carbon atoms as ring members, e.g. cyclopentylpropionic, cyclohexylacetic acid and the like, amonocyclic or bicyclic carbocyclic aryl carboxylic or carbocyclic aryllower aliphatic carboxylic acid, e.g. benzoic, dihydrocinnarnic, cinnamic, mandelic, salicylic, 4-aminosalicylic, Z-phenoxy-benzoic, 2-acetoxybenzoic, naphthoic acid, the acid formed by 3-hydroxy-2-naphthoic acid and formaldehyde and the like,-or a monocyclic or bicyclic carbocyclic aryl-dicarboxylic acid, e.g. phthalic acid and the like, a monocyclic or bicyclic heterocyclic aryl carboxylic acid, e.g. nicotinic, isonicotinic, 6-quinoline carboxylic, thienoic, furoic acid and the like, or any other suitable carboxylic acid, or an organic sulfonic acid, such as a lower alkane sulfonic acid, e.g. methane sulfonic, ethane sulfonic acid and the like, a lower alkane disulfonic acid, e.g. ethane 1,2-disulfonic acid and the like, a lower hydroxy-alkane sulfonic acid, eg. Z-hydroxyethane sulfonic acid and the like, a carbocyclic aryl sulfonic acid, such as a monocyclic carbocyclic aryl sulfonic acid, e.g. p-toluene sulfonic acid and the like.

A preferred method for the alleviation of pain comprises administering to a host requiring relief from pain a pharmaceutical composition consisting essentially of an effective amount of a non-toxic, pharmacologically and therapeutically acceptable acid addition salt of Z-aminoindane, such as the 2-amino-indane hydrochloride and the like.

The novel compositions consist essentially of an effective amount of the 2-amino-indane or a non-toxic, pharmacologically and therapeutically acceptable acid addition salt thereof, as the active ingredient.

Preferred compositions for the relief of pain are those which consist essentially of an effective amount of a nontoxic, pharmacologically and therapeutically acceptable acid addition salt of Z-amino-indane, such as the Z-aminoindane hydrochloride, as the active ingredient.

The active ingredient of such composition, the 2-aminoindane compound, is in no way structurally related to morphine or analogs thereof, and has structural features dissimilar to those of the known compounds of the analgesic-antipyretic group. We have now found that the compositions of this invention containing an effective amount of Z-amino-indane compound represent versatile tools in raising the threshold and suppressing the symptoms of many types of pain. Thus, they can be used to counteract light pain (e.g. toothaches, headaches and the like), as well as severe pain (e.g. post-operative pains, pains in connection with fractures and the like) and chronic pain (e.g. pains caused by arthritic conditions and the like). Light pains require correspondingly smaller doses of the active analgesic ingredient, whereas severe and chronic pains have to be counteracted with heavier doses of the active compound. Advantages of the compositions of this invention are the very infrequent occurrences of undesirable side-effects, and, for all practical purposes, the absence of any toxic properties. The

dosage of the compositions administered will, of course,

vary with the needs of each particular patient, and the attending physician can determine the proper amount necessary to provide the desired pain relief.

The compositions of the invention are prepared by combining the active ingredient with an inert pharmaceutically acceptable organic or inorganic carrier in specified proportions. The compositions of this invention may be made up to contain from about 0.5 to about 50 percent, by

Weight, of the active ingredient in the composition. Where the compositions are prepared for oral use (e.g. tablets, capsules and the like), the percentage, by weight of active ingredients, is from about 1 to about 50 percent, preferably from about 4 to about 30 percent of active material. In compositions prepared for injection (e.g. solutions and the like), the percentage by weight of active ingredient, is from about 0.5 to about 20 percent, preferably from about 1 percent to about 10 percent.

In preparing suitable, pharmaceutically acceptable dosage unit forms, any one of a wide variety of preparations may be manufactured, such as tablets, capsules, pills, solutions, suspensions and the like. In addition to the active ingredient, there may be present additional substances commonly employed in the pharmaceutical art for preparing dosage unit compositions. These may include excipients, binders, fillers, stabilizers, Wetting agents, emulsifiers, buffers, and/ or other inert ingredients. The active ingredient Z-amino-indane is normally utilized in the form of its therapeutically acceptable water-soluble salts, such as hydrochlorides, sulfates and the like, which represent the preferred forms of the active material for all pharmaceutical compositions.

The tablet, capsule, dragee and the like, provide for the preferred oral form of administration, which represents the most common application, particularly in the treatment of light or medium severe types of pain. These forms may be compounded to have from about 0.002 g. to about 0.075 g., especially from about 0.01 g. to about 0.05 g., of Z-amino-indane or preferably of a pharmacologically and therapeutically acceptable, non-toxic acid addition salt thereof, such as one of the above-mentioned .salts with an. inorganic or organic acid, e.g. hydrochloric,

sulfuric, phosphoric, D-tartaric, maleic, salicylic, 2- acetoxy-salicylic, methane sulfonic, p-toluene sulfonic acid and the like, as the active ingredient, per single dosage unit. The inert fillers, binders and other materials normally used for making tablets, capsules, dragees and the like, may be employed in formulating the latter. 1

Examples of these materials are corn starch, lactose, stearic acid, magesium stearate, talc, tragacanth, acacia, polyethylene glycol and the like. The'quantities of these ingredients may vary widely and depend, to some degree upon the kind, i.e. soft or hard, and the size of the desired tablet. Encapsulation may also be eifected using the same excipients as those used for tablets' As has been indicated above, the compounding is generally effected in the manner as that normally employed in the art. Any compatible colors, approved and certified under the provisions of the Federal Food, Drug and Cosmetic Law may be used for aesthetic purposes or as a means of identification.

Solutions for parenteral administration (which form of application is primarily used in the treatment of severe and chronic pains) have from about 0.005 g./ml. to about 0.15 g./ml., preferably from about 0.01 g./ml. to about 0.1 g./ml. of Z-arninoindane preferably in the form of a therapeutically acceptable acid addition salt thereof, such as one of the above-mentioned salts with an inorganic or organic acid, e.g. hydrochloric, sulfuric, phosphoric, D-tartaric, maleic, salicyclic, 2-acetoxy benzoic, methane sulfonic, p-toluene sulfonic acid and the like, as the pharmacologically active ingredient. Since the active ingredient, particularly an acid addition salt thereof, is a water-soluble substance, water (purified for the use in parenteral solutions) represents the primary solvent; other ingredients, particularly stabilizers, such as, for example, anti-oxidants, e.g. thiourea, sodium sulfide, sodium metabisulfite, ascorbic acid, cysteine hydrochloride, sodium formaldehyde sulfoXyla-te and the like, monothioglycerol, thiosorbitol and the like, buffer combinations, such as, for example, acetic acidzsodium acetate, potassium phthalate2sodium hydroxide, potassium dihydrogen phosphatezdi-sodiurn hydrogen phosphate, potassium dihydrogen phosphatezsodium hydroxide and the like, salts for making isotonic solutions, e.g. sodium chloride and the like, are added to ensure stable solutions for injection. It is desirable to maintain a pH of about 7 and any buffers yielding such pH may be utilized.

In addition to the analgesic Z-amino-indane compound and the inert pharmaceutical carrier, the pharmaceutical compositions of this invention may contain other pharmacologically active substances, for example, analgesic agents of the antipyretic type; such combination preparations are prepared according to procedures analogous to those used for known combination preparations. Additional pharmacologically active compounds, which may be used in combination with the Z-amino-indane ingredient of the compositions of this invention are, for example, analgesics of the anti-pyretic type, such as those previously mentioned, e.g. Z-acetoxy-benzoic acid, phenyl salicylate, cinchophen, acetophenetidine, aminopyrin, 4-

isopropyl-3-methyl-l,Z-diphenyl-pyrozolone and the like.

of the barbiturate-type, e.g. phenobarbital, diallyl barbituric acid and the like, or any other pharmacologically active compound, which is known to be suitable in combination compositions having the primarily analgesic effects.

This is a continuation-in-part application of our application Serial No. 112,495, filed May 25, 1961, which in turn is a continuation-in-part application of our application Serial No. 106,469, filed May 1, 1961, Which in turn is a continnation-in-part application of our application Serial No. 37,863, filed June 22, 1960, all now abandoned.

The following working examples are illustrative of the invention, but are'in no way intended to limit the present invention.

EXAMPLE 1 Tablets having 0.01 g. of 2-amino-indane hydrochloride as the active ingredient can be prepared as follows (for 10,000 tablets):

Ingredients G. 2-amino-indane hydrochloride 100.00 Corn starch 75.00 Lactose, spray dried 1317.00

Magnesium stearate, USP, 8.00

The Z-aJnino-indane hydrochloride is passedthrough a No. 40 screen; the other ingredients are passed through a No. 20 screen and mixed with the active ingredient in a suitable mixer. The resulting mixture is compressed into tablets, weighing 0.150 g., by using inch dies and standard concave punches (uppers bisected, lowers monogrammed) on a rotary tablet press.

EXAMPLE 2 Tablets having 0.015 g. of Z-amino-indane hydrochloride as the active ingredient can be prepared as follows (for 10,000 tablets):

The Z-amino-indane hydrochloride is screened through a No. 40 screen, and the lactose, tragacanth, talc and magnesium stearate are passed through a No. 20 screen; the combined materials are mixed for twenty minutes in a suitable mixer- The polyethyleneglycol is dissolved in a mixture of 50 ml. of water and 50 ml. of alcohol. The mixed powders are moistened with the resulting solution and mixed well until granules are formed. The moist mass is passed through a No. 10 screen and dried on trays with circulating dehumidified air at 38. The granules are then broken on a No. 16 screen and compressed into tablets weighing 0.2 g., using %2 inch dies, standard concave punches (upper bisected, lowers monogrammed), on a rotary tablet press.

EXAMPLE 3 Tablets having 001 g. of 2-amino-indanehydrochloride as the active ingredient can be prepared as follows The 2-amino-indane hydrochloride is passed through a No. 40 screen and the lactose and 38.5 g. of the corn starch are sieved through a No. 20 screen. The resulting materials are blended for twenty minutes in a suitable mixer. 28.6 gof corn starch is suspended in 35 ml. of cold water and a paste is formed by adding 140 ml. of boiling water. The paste is added to the mixed powders and granules are formed by mixing. The moist mass is passed through a No. 8 screen and dried on trays with circulating, dehumidified air at 38; the granules are broken on a No. 16 screen, the material is returned to the mixer, the stearic acid is added through a No. 20 screen and the mixture is blended for twenty minutes. The resulting product is compressed into tablets, weighing 0.15 g., using inch dies, flat, beveled-edge punches, uppers bisected, lowers monogrammed, on a rotary tablet press.

EXAMPLE 4 Tablets having 0.025 g. of Z-aminodndane hydrochloride as the active ingredient are prepared as follows (for 3 ,200 tablets) Ingredients:

Z-amino-indane hydrochloride g 80.00 Tragacanth g 16.00 Lactose, spray dried g 6 32.00 Talc g 24.00 Corn starch g 40.00 stearic acid g 4.00 Magnesium stearate g 4.00

Purified water ml 100.00

EXAMPLES An injeotable solution having 0.01 g./m1. of Z-a-minoindane hydrochloride as the activein-gredientcan be prepared as follows (for 1,000 ml.)

Ingredients:

.2-amino-indane hydrochloride g 10.00 Sodium chloride, USP g 9.00 Water for injection, USP, q.s rnl 1000.00

The 2-amino-indane hydrochloride and the sodium chloride are dissolved in sufiicient water for injection to make a total volume of 1000.00 ml. The solution is filtered through a'medium porosity sintered glass filter. Portions of 1.1 ml. of the solution are filled into ampules, which aresealed and sterilized in an autoclave at for thirty minutes.

' EXAMPLE 6 An injectable solution having 0 .05 g./ ml. of Z-amino} indane hydrochloride as the active ingredient is prepared as follows (for 1,000 ml.):

Ingredients:

Z-aminO-indane hydrochloride g 50.00 Sodium chloride, USP g 45.00 Water for injection, USP, q.s rnl 1000.00

The parenteral solution having 005 g./ml. of the active ingredient is prepared as described in Example 5.

The active compounds. used in the compositions of the invention may be prepared as follows:

EXAMPLE A A solution of 14.8 g. of Z- indanone in 75 mol. of pyridine is added to a solution of 9.35 g. of hydroxylamine hydrochloride in 50ml. aqueous ethanol, and the mixtureis allowed to stand for two days at roomtemperature. The precipitate, formed after being poured onto 7 ice-water, is filtered off and then air dried to yield the 2-oximino-indane, M.P. 150-154 yield: 92.3 percent.

A solution of 7.6 g. of 2-oximino-indane in a mixture of 150 ml. of ethanol and 21.75 ml. of a 7.1 N solution of hydrogen chloride in ethanol is treated with hydrogen in the presence of 0.75 g. of a palladium catalyst (20 percent palladium on charcoal). The catalyst is filtered olLthe filtrate is concentrated and the resulting Z-aminoindane hydrochloride of the formula:

GHNH3 .HOl

is recrystallized from a mixture of ethanol and ethyl acetate, MP. 233240.

The free base may be obtained from the hydrochloride by treating an aqueous solution of the latter with aqueous ammonia and extracting the liberated Z-amino-indane with diethyl ester. From the free base other salts, such as the Z-amino-indane sulfate, 2-amino-indane phosphate and the like, can be prepared by reacting Z-amino-indane with the appropriate acids, such as sulfuric, phosphoric acid and the like, in an appropriate medium.

Also included within the scope of this invention are the new non-toxic, pharmacologically and therapeutically acceptable addition saltsof 2-amino-indane with organic carboxylic acids or organic sulfonic acids; organic carboxylic and organic sulfonic acids are primarily those mentioned hereinbefore. These salts may be prepared according to known methods, for example, by reacting 2- amino indane with an organic carboxylic acid or an organic sulfonic acid, or by converting an acid addition salt of 2-amin0-indane into an acid addition salt with an organic carboxylic acid or an organic sulfonic acid. The formation of the salt is preferably carried out in the presence of an inert solvent, e.g. ethanol, acetone and the like; if necessary, the solvent may be removed (for example, byevaporating the solvent) to obtain a crys talline salt. An acid addition salt may be converted into another salt, for example, by reacting it with a metal salt, particularly an alkali metal, e.g. sodium, potassium and the like, salt of an organic carboxylic acid or an organic sulfonic acid in the presence of a suitable inert solvent or solvent mixture.

The manufacture of salts of Z-arnino-indane may be illustrated by the following example:

EXAMPLE B To a solution of 0.5 g. of 2-amino-indane in 5 ml. of acetone is added 0.45 g. of maleic acid in 5 ml. of acetone; the crystalline Z-amino-indane maleate precipitates and is filtered off, M.P. 150-152. 1

Other salts of Z-amino-indane with organic carboxylic acids, for example, the Z-amino-indane D-tartrate (M.P. ZOO-202), the Z-amino-indane salicylate (MP. 124-- 126), Z-amino-indane 2-acetoxy-benzoate (MP. 89- 91") and the like are prepared as shown hereinabove.

To a solution of 0.5 g. of, 2-amino-indane in 5 ml. of acetone is added 0.4 g. of methane sulfonic acid (in the form of an 80 percent aqueous solution); the desired 2- amino-indane methane sulfonate crystallizes and is filtered off, M.P. 189-191".

Other salts of Z-amino-indane with organic sulfo-nic acids, such as, for example, the Z-amino-indane p-toluene sulfonate (M.P. 214216) and the like are prepared according to methods analogous to those described hereinabove.

The salts of Z-amino-indane with organic carboxylic acids or with organic sulfonic acids, particularly those described hereinabove, may replace the Z-amino-indane hydrochloride used in the previously described pharmaceutical compositions:

8 EXAMPLE 7 Tablets having 0.025 g. of Z-amino-indane maleate as the active ingredient as prepared as follows (for 3,200 tablets):

Water, purified ml 100.00

Tablets weighing 0.25 g. are prepared as described in Example 4.

.- EXAMPLE 8 Tablets containing 0.025 g. of Z-amino-indane 2-ac'etoxy-benzoate as the active ingredient are prepared as follows (for 6,400 tablets):

Ingredients:

Z-aminO-indane 2-acetoxy-benzoate g 160.00 Tragacanth g 32.00 Lactose, spray dried ....g 1264.00 Talc g 48.00 Corn starch g 80.00 Stearic acid g 8.00 Magnesium stearate g 8.00

Purified water rnl 200.00

Tablets weighing 0.25 g. are prepared as described in Example 4.

EXAMPLE 9 Tablets having 0.025 g. of Z-amino-indane methane sulfonate as the active ingredient may be prepared as follows (for 3,200 tablets):

Ingredients:

Z-arnino-indane methane sulfonate g 80.00 Tragacanth g 16.00 Lactose, spray dried g 632.00 Talc g 24.00 Corn starch ..-g 40.00 Stearic acid g 4.00 Magnesium stearate g 4.00 Water, purified ml 100.00

Tablets weighing 0.2 g. are prepared as shown in Example 4.

What is claimed is:

1. A method for the alleviationof pain, which comprises administering to a host requiring relief from pain, an oral composition having analgesic elfects, consisting essentially of about 0.01 g. to about 0.05 g. of a member selected from the group consisting of Z-aminO-indane and a non-toxic, pharmacologically and therapeutically acceptable acid addition salt thereof, per single dosage unit.

2. A method for the alleviation of pain, which comprises administering to a host requiring relief from pain, an oral composition having analgesic elfects, consisting es sentially of about 0.01 g. to about 0.05 g. of Z-aminoindane hydrochloride, per single dosage unit.

,3. A method for the alleviation of pain, which comprises administering to a host requiring relief from pain, a parenteral composition having analgesic effects, consisting essentially of about 0.01 g./ml. to about 0.1 g./ml. of a member selected from the group consisting of 2- amino-indane and a non-toxic, pharamacologically and therapeutically acceptable acid addition salt thereof.

4. A method for the alleviation of pain, which comprises administering to a host requiring relief from pain, a parenteral composition having analgesic effects, consisting essentially of about 0.01 g./ml. to about 0.1 g./ml. of 2-amino-indane hydrochloride.

(References on following page) References Cited in the file of this patent UNITED STATES PATENTS Goldberg Sept. 27, 1949 Allen Jan. 30, 1951 Ott Apr. 17, 1956 Reichter May 28, 1957 Sahyun June 16, 1959 Harwood Aug. 18, 1959 Schenck Dec. 8, 1959 10 FOREIGN PATENTS Germany Mar. 8, 1956 OTHER REFERENCES 

1. A METHOD FOR THE ALLEVIATION OF PAIN, WHICH COMPRISES ADMINISTERING TO A HOST REQUIRING RELIEF FROM PAIN, AN ORAL COMPOSITION HAVING ANALGESIC EFFECTS, CONSISTING ESSENTIALLY OF ABOUT 0.01 G. TO ABOUT 0.05 G. OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF 2-AMINO-INDANE AND A NON-TOXIC, PHARMACOLOGICALLY AND THERAPEUTICALLY ACCEPTABLE ACID ADDITION SALT THEREOF, PER SINGLE DOSAGE UNIT. 